This invention relates to the synthesis of high purity N-benzyloxycarbonyl-L-aspartic acid (Z-Asp) suitable for use in the production of L-aspartyl-L-phenylalanine methyl ester, an artificial sweetener, and more particularly to a method of synthesizing highly pure N-benzyloxycarbonyl-L-aspartic acid at high temperatures.
L-Aspartyl-L-phenylalanine methyl ester, aspartame, is known to be about 160 times sweeter than sucrose in aqueous solution. Thus, the use of aspartame as a low-calorie sweetener makes it a highly desirable end product. Aspartame is generally prepared from Z-Asp. In view of the end use of aspartame in food products as a sugar substitute, the Z-Asp must be as pure as possible and substantially free of by-products generally formed during the formation of the Z-Asp, such as the dipeptide, N-benzyloxycarbonyl aspartyl aspartic acid (Z-Asp-Asp) and sodium chloride.
The reaction of benzyl chloroformate (BCF) with L-aspartic acid (L-AA) to yield Z-Asp has been well known for a number of years. The chemical literature discloses that Z-Asp may be synthesized by the condensation of L-AA with BCF in an alkaline medium. Prior to 1981, the processes described in the literature did not mention the reaction conditions needed to produce Z-Asp with relatively small amounts of by-products.
U.S. Pat. No. 4,293,706 which issued on Oct. 6, 1981 to Gorman, et al. teaches that Z-Asp can be prepared substantially free of Z-Asp-Asp by reacting BCF with the disodium salt of L-AA in an alkaline aqueous system within a specific pH range of between 10.75 and 11.75, and preferably 11.50 to 11.75. The temperature of the reaction is maintained between 10.degree. and 45.degree. C., preferably at room temperature, at which each of the working examples is run. The resulting reaction mixture is acidified to convert the product to the free acid. The patentees caution at column 2, lines 17-25 that when the reaction conditions vary, such as a pH of over 12, significant hydrolysis of the benzyl chloroformate occurs, the Z-Asp product contains more than trace amounts of impurities and the yield is reduced. At column 3, lines 15-22, they also note that as the temperature of the reaction increases, the amount of impurities in the Z-Asp product increases.
U.S. Pat. No. 4,345,091 issued on Aug. 17, 1982 to Sugiyama, et al. claims that high yields of Z-Asp can be obtained by reacting BCF with a sodium or potassium salt of L-AA by carrying out the reaction with the pH maintained within the specific range of 12.0 to 13.5 throughout the reaction. Sugiyama, et al. teach maintaining the temperature of the reaction mixture at 10.degree.-30.degree. C. for 3 hours. The results show increased levels of Z-Asp-Asp when the pH falls below 12.0 together with a decrease in yield. Levels of unreacted L-AA in the Z-Asp crystals are reported to be 0.6 percent and above.
Both the Gorman, et al. and Sugiyama, et al. patentees provide suitable reaction conditions within narrow specific pH ranges for preparing a relatively pure Z-Asp product with relatively small amounts of Z-Asp-Asp by-product. However, it remains desirable to increase further the yield and purity as well as providing other improvements in the synthesis of Z-Asp, such as decreasing the reaction time. Accordingly, it is desirable to provide a method of preparing Z-Asp product at faster rates and containing lesser amounts of unreacted L-aspartic acid than heretofore thought possible.